The long-term objective of this work is to increase our fundamental understanding of ventricular fibrillation (VF) by mapping cardiac activation. During the last grant period, we constructed a mapping system that records from over 500 channels simultaneously and developed software techniques that allow us to quickly animate and quantify cardiac activation sequences during VF. These advances have allowed us to make several important new observation about VF, including the following: (1) VF is not a single entity with a fixed level of disorganization but is influenced by numerous factors, such as the duration of VF and drugs. (2) beta agonists and antagonists significantly alter activation sequences during VF, but in ways that are not diametrically opposite each other. (3) It is possible to capture an epicardial region greater than 5cm2 in area by pacing during VF. These findings have caused us to ask new, more focused questions that only can be answered with a mapping system that can record from 500 channels or more. Is VF maintained by 5 to 10 reentrant circuits whose pathways are centimeters in length instead of 10s or 100s of circuits with pathways millimeters long? Are adjacent reentrant circuits coupled so that they tend to be in phase? Do VF activation fronts frequently arise in a particular cardiac region, i.e. the Purkinje fibers or the left ventricular apex? In the presence of infarction, is the number of activation fronts decreased outside the infarcted area? Will VF activation fronts become more complex and fractionated in the presence of the patchy fibrosis of ischemic cardiomyopathy? In dialated hypertrophy, will stretched myofibers give rise to focal activation during VF? Do certain class III drugs cut the number of VF reentrant circuits in half? Can two drugs each of which increases the wavelength of a reentrant circuit and/or decreases the number of VF activation fronts by a different mechanism, prevent sustained VF? Can rapid simultaneous pacing from six to ten sites throughout the ventricles halt VF, either along or with drugs? The basic understanding of the fundamental mechanisms of VF gained from this work should aid in the development of rational therapy to prevent and halt the number one health problem in the United States today, sudden cardiac death.